The proposal is to continue our studies of the "minimal model method" for assessing metabolic function in vivo. This method uses computer modeling to analyze the dynamics of glucose and insulin observed in vivo, during the frequently-sampled intravenous glucose tolerance test (FSIGT). From the analysis, 5 "characteristic parameters" of metabolic regulation are calculated. Taken together, these parameters are suggested as a comprehensive metabolic protrait of a single individual. Of major significance is SI, the insulin sensitivity index. Having previously demonstrated a strong correlation between SI from the FSIGT and an analagous glucose clamp parameter, we now propose to measure SI directly. This will require a series of special euglycemic and hyperglycemic glucose clamps to be performed in conscious dogs. Insulin will be infused at various rates directly into the portal vein, so that results can be compared with endogenous (i.e., intraportal) insulin appearance in the FSIGT. From the clamps, a complete "map" will be obtained of the effects of glucose and insulin on glucose disappearance, in the physiological concentration range. We will test the hypotheses that 1) SI from the clamp experiments can be said to define insulin sensitivity over the physiological range of glycemia and insulinemia; and 2) that SI from clamps equals the same parameter from the FSIGT. By pharmacological means, we will prepare animals with 1) Beta-cell dysfunction, 2) insulin resistance, and 3) both, and attempt to validate SI in pathophysiological states. Third, we will measure the sensitivity of first and second-phase insulin secretion to glucose using hyperglycemic glucose clamps, and compare the results with pancreatic parameters 01 and 02 from the FSIGT analysis. Fourth, we propose to adapt the minimal model approach to the oral glucose tolerance test, so that physiological indices of metabolic function can be calculated from the OGTT, instead of the usual empirical indices of glucose tolerance.